Hans-Georg Olbrich

Intra-aortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock (IABP-SHOCK II): final 12 month results of a randomised, open-label trial

BACKGROUND In current international guidelines the recommendation for intra-aortic balloon pump (IABP) use has been downgraded in cardiogenic shock complicating acute myocardial infarction on the basis of registry data. In the largest randomised trial (IABP-SHOCK II), IABP support did not reduce 30 day mortality compared with control. However, previous trials in cardiogenic shock showed a mortality benefit only at extended follow-up. The present analysis therefore reports 6 and 12 month results. METHODS The IABP-SHOCK II trial was a randomised, open-label, multicentre trial. Patients with cardiogenic shock complicating acute myocardial infarction who were undergoing early revascularisation and optimum medical therapy were randomly assigned (1:1) to IABP versus control via a central web-based system. The primary efficacy endpoint was 30 day all-cause mortality, but 6 and 12 month follow-up was done in addition to quality-of-life assessment for all survivors with the Euroqol-5D questionnaire. A masked central committee adjudicated clinical outcomes. Patients and investigators were not masked to treatment allocation. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00491036. FINDINGS Between June 16, 2009, and March 3, 2012, 600 patients were assigned to IABP (n=301) or control (n=299). Of 595 patients completing 12 month follow-up, 155 (52%) of 299 patients in the IABP group and 152 (51%) of 296 patients in the control group had died (relative risk [RR] 1·01, 95% CI 0·86-1·18, p=0·91). There were no significant differences in reinfarction (RR 2·60, 95% CI 0·95-7·10, p=0·05), recurrent revascularisation (0·91, 0·58-1·41, p=0·77), or stroke (1·50, 0·25-8·84, p=1·00). For survivors, quality-of-life measures including mobility, self-care, usual activities, pain or discomfort, and anxiety or depression did not differ significantly between study groups. INTERPRETATION In patients undergoing early revascularisation for myocardial infarction complicated by cardiogenic shock, IABP did not reduce 12 month all-cause mortality. FUNDING German Research Foundation; German Heart Research Foundation; German Cardiac Society; Arbeitsgemeinschaft Leitende Kardiologische Krankenhausärzte; University of Leipzig--Heart Centre; Maquet Cardiopulmonary; Teleflex Medical.

Intraaortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock: Design and rationale of the Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial

BACKGROUND In current guidelines, intraaortic balloon pumping (IABP) is considered a class 1 indication in cardiogenic shock complicating acute myocardial infarction. However, evidence is mainly based on retrospective or prospective registries with a lack of randomized clinical trials. Therefore, IABP is currently only used in 20% to 40% of cardiogenic shock cases. The hypothesis of this trial is that IABP in addition to early revascularization by either percutaneous coronary intervention or coronary artery bypass grafting will improve clinical outcome of patients in cardiogenic shock. STUDY DESIGN The IABP-SHOCK II study is a 600-patient, prospective, multicenter, randomized, open-label, controlled trial. The study is designed to compare the efficacy and safety of IABP versus optimal medical therapy on the background of early revascularization by either percutaneous coronary intervention or coronary artery bypass grafting. Patients will be randomized in a 1:1 fashion to 1 of the 2 treatments. The primary efficacy end point of IABP-SHOCK II is 30-day all-cause mortality. Secondary outcome measures, such as hemodynamic, laboratory, and clinical parameters, will serve as surrogate end points for prognosis. Furthermore, an intermediate and long-term follow-up at 6 and 12 months will be performed. Safety will be assessed, by the GUSTO bleeding definition, peripheral ischemic complications, sepsis, and stroke. CONCLUSIONS The IABP-SHOCK II trial addresses important questions regarding the efficacy and safety of IABP in addition to early revascularization in patients with cardiogenic shock complicating myocardial infarction.

Vitamins C and E protect isolated cardiomyocytes against oxidative damage.

There is considerable evidence that oxygen free radicals are involved in reperfusion injury of ischemic myocardium. Epidemiologic studies showed an inverse correlation between plasma levels of alpha-tocopherol (vitamin E) and ascorbic acid (vitamin C) and mortality from ischemic heart disease. The present study examines the influence of both vitamins on the toxic effects of singlet oxygen on isolated rat cardiomyocytes. Freshly isolated cardiomyocytes from adult rats were exposed to singlet oxygen which was generated by photoactivation of the photosensitive dye rose bengal (10(-7) M). This procedure induced irreversible hypercontracture in about 95% of rod-shaped cardiomyocytes within 15 min after onset of photoactivation of rose bengal. Pretreatment with vitamin C (10(-5) to 10(-2) M) or E (10(-6) to 10(-3) M) reduced the number of hypercontracted cells after exposure to singlet oxygen in a concentration-dependent manner. Simultaneous application of both vitamins (vitamin E 10(-6) M plus vitamin C 10(-5) M or vitamin E 10(-5) M plus vitamin C 10(-4) M) revealed a marked overadditive protective effect against oxidative damage as compared with the single application of each vitamin. Our data show that alpha-tocopherol and ascorbic acid exert direct protective actions on isolated cardiomyocytes against oxidative damage and provide an overadditive effect if administered simultaneously.

Ratio of pyramidal cells versus non-pyramidal cells in sector CA1 of the human Ammon's horn.

SummaryCombined Golgi/pigment studies revealed that pyramidal neurons and non-pyramidal cells of the Ammons horn of the human adult can be distinguished from each other by their characteristic lipofuscin pigment deposits. In sector CA1, both the typical pyramidal neurons and the modified forms of pyramidal cells contain a modest amount of fine lipofuscin granules while non-pyramidal cells are either pigment-laden or devoid of lipofuscin deposits. Strips running through the whole depth of the pyramidal cell layer and the stratum oriens of CA1 were examined and all nucleolated nerve cells present within these strips were classified and counted (16 brains, age range from 28 to 69 years). Of the 18,510 neurons classified, 16,765 were pyramidal cells, including their modified versions, and 1,745 were non-pyramidal cells. The pyramidal cells, accordingly, were intermixed with 9.4±1.0% non-pyramidal neurons. The data presented provide a basis for investigation of the aging and diseased human brain.

Beat-to-beat variation of heart rate in diabetic patients with autonomic neuropathy and in completely cardiac denervated patients following orthotopic heart transplantation.

Dysfunction of the vagal nerve, an early symptom in the development of autonomic neuropathy, can be assessed reliably by the beat-to-beat variation in heart rate. Patients after a cardiac transplantation are a unique model to investigate the beat-to-beat variation of a completely denervated heart. Heart rate and the beat-to-beat variation during normal and deep respiration were investigated in diabetic subjects with an autonomic neuropathy (n = 10), age and sex matched healthy controls (n = 10) and cardiac transplanted patients (n = 10). Further studies during pharmacological blockade of the parasympathetic nervous system with atropine were performed. In the denervated heart the coefficient of variation of the beat-to-beat interval was 0.38 +/- 0.02% during normal respiration, compared to 1.32 +/- 0.13% (P less than 0.0001) and 2.56 +/- 0.13% (P less than 0.0001) in the diabetic and control subjects, respectively. Administration of atropine (2 mg intravenously) decreased the coefficient of variation of the RR-interval to 0.73 +/- 0.09% in the diabetic patients (P less than 0.0005) and to 0.67 +/- 0.07% in the controls (P less than 0.0001), whereas the coefficient of variation remained unaffected in the cardiac denervated patients (0.39 +/- 0.02%). In the three groups an almost parallel increase of the RR-variation was observed during deep respiration at a rate of 6 breaths/min (from 0.38 +/- 0.02% to 1.99 +/- 0.38% in cardiac transplanted patients, P less than 0.0025; from 1.32 +/- 0.13% to 3.10 +/- 0.43% in diabetic patients, P less than 0.0025; from 2.56 +/- 0.13% to 5.42 +/- 0.94% in healthy controls, P less than 0.005). We conclude that a beat-to-beat variation of heart rate is present in the completely denervated heart. This RR-variation can not be influenced by a pharmacological blockade of the parasympathetic nervous system with atropine. The beat-to-beat variation increases during deep respiration not only in healthy controls but also in diabetic patients with autonomic neuropathy (partially denervated hearts) and cardiac transplanted patients (completely denervated hearts). This indicates an intracardiac mechanism in the modulation of heart rate.

Variations of segmental endothelium-dependent and endothelium-independent vasomotor tone after cardiac transplantation (qualitative changes in endothelial function)

Endothelial dysfunction is a common phenomenon after cardiac transplantation. However, qualitative differences in endothelial vasoregulation at different coronary segments and at different postoperative times have rarely been explored. To uncover the functional variations of endothelium responses we infused the endothelium-dependent vasodilator acetyl-choline (50 micrograms) followed by the endothelium-independent vasodilator 3-morpholinosydnonimine (SIN-1) (1 mg; 16 patients) or nitroglycerin (0.3 mg; 14 patients) sequentially into the left coronary artery. We investigated the responses of 120 nonstenotic coronary segments (proximal and distal left anterior descending and right circumflex coronary arteries) in 30 patients with quantitative angiography (group 1: 13 patients, 12 +/- 1 months after cardiac transplantation; group 2: 17 patients, 55 +/- 3 months after cardiac transplantation). Continuous-flow measurement was performed to exclude significant reduction of microvascular response influencing epicardial dilation. Five responses to acetylcholine administration followed by nitrates were observed. On the one end of the spectrum, segments dilate to acetylcholine administration with no further dilation to exogenous nitric oxide, indicating completely preserved endothelial function. On the other end, segments constrict to acetylcholine with no change after endogenous nitric oxide, reflecting a defective endothelial and defective smooth muscle function. The different patterns of coronary vasomotor lone responses to endogenous nitric oxide followed by exogenous nitric oxide represent different degrees of endothelial function after cardiac transplantation. In addition, the functional assessment of endothelial integrity shows qualitative time-dependent differences between proximal and distal coronary parts. The existence of coronary segments with functioning endothelium indicates that the latter is not diffusely disturbed in all cardiac transplant recipients and that the endothelial damage is perhaps not irreversibly lost.

Glutamic acid decarboxylase immunoreactivity in sector CA 1 of the human Ammon's horn

SummaryThe distribution of glutamic acid decarboxylase (GAD) immunoreactive neurons, fibres and punctae in sector CA 1 of the adult human Ammons horn was studied in Vibratome sections (40 μm thick) of tissue obtained at surgery and autopsy. On light microscopical examination, the materal did not show pathological changes. The antibody was visualized by the unlabelled antibody enzyme method. GAD-immunoreactive neurons, fibres and punctae were present in all layers. Most immunoreactive neurons were located in the stratum pyramidale and stratum lacunosum. Their size ranged from 8 μm in the stratum lacunosum to about 50 μm in the stratum oriens. The somata offered a wide range of shapes, multiform to fusiform with the long axis aligned parallel or vertically to the alveus. All somata belonged to the heterogeneous group of non-pyramidal neurons. The dendrites either radiated in all directions or tended to run in two opposite directions. After bleaching the chromogen and staining for lipofuscin pigment granules and basophilic material, it turned out that within the stratum pyramidale all formerly GAD-immunoreactive neurons belonged to the group of lipofuscin-laden non-pyramidal neurons. Within the other layers, a few formerly GAD-immunoreactive neurons were devoid of lipofuscin pigment. The highest density of GAD-immunoreactive punctae was found in the stratum lacunosum. In addition to numerous GAD-immunoreactive punctae in the pyramidal layer and in the stratum radiatum there were thin GAD-immunoreactive fibres of varying length extending into various directions.

Efficiency of β-adrenoceptor subtype coupling to cardiac adenylyl cyclase in cardiomyopathic and control hamsters

Densities of beta-adrenoceptor subtypes and their contributions to stimulation of adenylyl cyclase were studied in heart ventricles from cardiomyopathic (BIO 8262) and control Syrian hamsters (CLAC) at 4 different ages: 30, 100, 200, and 300 days. In BIO ventricles neither total beta-adrenoceptor density nor that of the beta 1-adrenoceptor subtype differed from the controls, whereas the density of beta 2-adrenoceptors was significantly higher in myocardium from 200- and 300-day-old BIO compared to that from age-matched CLAC hamsters. Stimulation of adenylyl cyclase by the non-selective beta-adrenoceptor agonist isoprenaline did not differ between strains, but the beta 1-adrenoceptor mediated component was significantly reduced in cardiomyopathic hamsters of all age groups. In 300-day-old animals beta 1-adrenoceptors accounted for 83% (CLAC) and 68% (BIO) of total beta-adrenoceptor binding sites, whereas only 26% (CLAC) and 6% (BIO) of the isoprenaline effect on cAMP formation were mediated via beta 1-adrenoceptors. Thus, the present study shows a lower coupling efficiency of beta 1-adrenoceptors compared to the beta 2-adrenoceptor subtype in ventricles from healthy Syrian hamsters and a progressive, further reduction in beta 1-adrenergic function in cardiomyopathic animals.

Uncoupling of β1-adrenoceptors from cardiac adenylyl cyclase in cardiomyopathic and control hamsters

The beta-adrenoceptor-adenylyl cyclase system was studied in heart ventricles from Wistar rats, cardiomyopathic (BIO 8262) and nonfailing control hamsters (CLAC) using the beta 1-adrenoceptor antagonist CGP 20712A. In radioligand binding studies, the majority of beta-adrenoceptors in ventricles from rats as well as from CLAC hamsters was of the beta 1-subtype (72.2% and 76.6%, respectively). In BIO ventricles a significant (CLAC vs. BIO, P < 0.05) reduction in the beta 1-subtype (62.9%) was found. In Wistar rats the subtype-mediated stimulation of adenylyl cyclase reflected the beta 1:beta 2 ratio as determined by binding studies. In hamster ventricles the effect of isoprenaline was mediated predominantly (CLAC) or exclusively (BIO) via the beta 2-subtype, indicating that cardiac beta 1-adrenoceptors were partly (CLAC) or completely (BIO) uncoupled from the adenylyl cyclase.

ADP receptor antagonists in patients with acute myocardial infarction complicated by cardiogenic shock: a post hoc IABP-SHOCK II trial subgroup analysis.

AIMS The aim of this post hoc subgroup analysis of the Intraaortic Balloon Pump in Cardiogenic Shock II trial was to compare the clinical outcome of patients treated with either clopidogrel or the newer, more potent P2Y12 receptor inhibitors prasugrel or ticagrelor. METHODS AND RESULTS The primary endpoint was one-year mortality with respect to different P2Y12 receptor inhibitors. Secondary safety endpoints were GUSTO bleedings until hospital discharge. After exclusion of 117 patients (patients who died before or during PCI, patients with unavailable information on P2Y12 receptor inhibitor treatment, patients not receiving or receiving a combination of different P2Y12 receptor inhibitors as acute antiplatelet therapy), 483 patients were analysed. Of these, 373 patients (77.2%) received clopidogrel and 110 patients (22.8%) either prasugrel or ticagrelor as acute antiplatelet therapy. The adjusted rate of mortality did not differ between prasugrel/ticagrelor and clopidogrel treated patients (HR: 0.83, 95% CI: 0.59-1.19, padj=0.31). GUSTO bleedings did not differ between groups (14.3% for prasugrel/ticagrelor and 16.4% for clopidogrel, HR: 0.91, 95% CI: 0.55-1.5, padj=0.7). CONCLUSIONS This IABP-SHOCK II trial subgroup analysis shows that the use of potent P2Y12 receptor inhibitors like prasugrel or ticagrelor is feasible and might not be harmful in selected patients with cardiogenic shock complicating acute myocardial infarction. However, the superiority in comparison to clopidogrel remains to be proven.